Developing an intervention to optimise the outcome of cardiac surgery in people with diabetes: the OCTOPuS pilot study.

BACKGROUND: Cardiothoracic surgical outcomes are poorer in people with diabetes compared with those without diabetes. There are two important uncertainties in the management of people with diabetes undergoing major surgery: (1) how to improve diabetes management in the weeks leading up to an elective procedure and (2) whether that improved management leads to improved postoperative outcomes. The aim of this study was to develop and pilot a specialist diabetes team-led intervention to improve surgical outcomes in people with diabetes. DESIGN: Open pilot feasibility study SETTING: Diabetes and cardiothoracic surgery departments, University Hospital Southampton NHS Foundation Trust PARTICIPANTS: Seventeen people with diabetes undergoing cardiothoracic surgery INTERVENTION: Following two rapid literature reviews, a prototype intervention was developed based on a previously used nurse-led outpatient intervention and tested. PRIMARY OUTCOME: Feasibility and acceptability of delivering the intervention SECONDARY OUTCOMES: Biomedical data were collected at baseline and prior to surgery. We assessed how the intervention was used. In depth qualitative interviews with participants and healthcare professionals were used to explore perceptions and experiences of the intervention and how it might be improved. RESULTS: Thirteen of the 17 people recruited completed the study and underwent cardiothoracic surgery. All components of the OCTOPuS intervention were used, but not all parts were used for all participants. Minor changes were made to the intervention as a result of feedback from the participants and healthcare professionals. Median (IQR) HbA1c was 10 mmol/mol (3, 13) lower prior to surgery than at baseline. CONCLUSION: This study has shown that it is possible to develop a clinical pathway to improve diabetes management prior to admission. The clinical and cost-effectiveness of this intervention will now be tested in a multicentre randomised controlled trial in cardiothoracic centres across the UK. TRIAL REGISTRATION: ISRCTN; ISRCTN10170306 . Registered 10 May 2018.

The Optimising Cardiac Surgery ouTcOmes in People with diabeteS (OCTOPuS) randomised controlled trial to evaluate an outpatient pre-cardiac surgery diabetes management intervention: a study protocol.

INTRODUCTION: Cardiothoracic surgical outcomes are poorer in people with diabetes compared with those without diabetes. There are two important uncertainties in the management of people with diabetes undergoing major surgery: (1) how to improve diabetes management in the weeks leading up to an elective procedure and (2) whether that improved management leads to better postoperative outcomes. We previously demonstrated the feasibility of delivering the Optimising Cardiac Surgery ouTcOmes in People with diabeteS (OCTOPuS) intervention, an outpatient intervention delivered by diabetes healthcare professionals for people with suboptimally managed diabetes over 8-12 weeks before elective cardiac surgery. The present study will assess the clinical and cost-effectiveness of the intervention in cardiothoracic centres across the UK. METHODS AND ANALYSIS: A multicentre, parallel group, single-blinded 1:1 individually randomised trial comparing time from surgery until clinically fit for discharge in adults with suboptimally managed type 1 diabetes or type 2 diabetes undergoing elective surgery between the OCTOPuS intervention and usual care (primary endpoint). Secondary endpoints will include actual time from surgery to discharge from hospital; days alive and either out of hospital or judged as clinically fit for discharge; mortality; time on intensive therapy unit (ITU)/ventilator; infections; acute myocardial infarction; change in weight; effect on postoperative renal function and incidence of acute kidney injury; change in HbA1c; frequency and severity of self-reported hypoglycaemia; operations permanently cancelled for suboptimal glycaemic levels; cost-effectiveness; psychosocial questionnaires. The target sample size will be 426 recruited across approximately 15 sites. The primary analysis will be conducted on an intention-to-treat population. A two-sided p value of 0.05 or less will be used to declare statistical significance for all analyses and results will be presented with 95% CIs. ETHICS AND DISSEMINATION: The trial was approved by the South Central-Hampshire A Research Ethics Committee (20/SC/0271). Results will be disseminated through conferences, scientific journals, newsletters, magazines and social media. TRIAL REGISTRATION NUMBER: ISRCTN10170306.

Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease.

BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is a hematologic illness involving cytokine-induced lymphoproliferation, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. The molecular underpinnings of interleukin-6(IL-6)-blockade refractory patients remain unknown; no targeted therapies exist. In this study, we searched for therapeutic targets in IL-6-blockade refractory iMCD patients with the thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, organomegaly (TAFRO) clinical subtype. METHODS: We analyzed tissues and blood samples from three IL-6-blockade refractory iMCD-TAFRO patients. Cytokine panels, quantitative serum proteomics, flow cytometry of PBMCs, and pathway analyses were employed to identify novel therapeutic targets. To confirm elevated mTOR signaling, a candidate therapeutic target from the above assays, immunohistochemistry was performed for phosphorylated S6, a read-out of mTOR activation, in three iMCD lymph node tissue samples and controls. Proteomic, immunophenotypic, and clinical response assessments were performed to quantify the effects of administration of the mTOR inhibitor, sirolimus. RESULTS: Studies of three IL-6-blockade refractory iMCD cases revealed increased CD8+ T cell activation, VEGF-A, and PI3K/Akt/mTOR pathway activity. Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels. Sirolimus induced clinical benefit responses in all three patients with durable and ongoing remissions of 66, 19, and 19 months. CONCLUSION: This precision medicine approach identifies PI3K/Akt/mTOR signaling as the first pharmacologically-targetable pathogenic process in IL-6-blockade refractory iMCD. Prospective evaluation of sirolimus in treatment-refractory iMCD is planned (NCT03933904). FUNDING: Castleman's Awareness & Research Effort/Castleman Disease Collaborative Network, Penn Center for Precision Medicine, University Research Foundation, Intramural NIH funding, and National Heart Lung and Blood Institute.

International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease.

Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8-negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti-interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.

Parkinsonian signs are a risk factor for falls.

BACKGROUND: Parkinsonian signs are common, non-specific findings in older adults and associated with increased rates of dementia and mortality. It is important to understand which motor outcomes are associated with parkinsonian signs. OBJECTIVES: To determine the role of parkinsonian signs on fall rates among older adults. METHODS: We conducted a longitudinal study of primary care patients from the University of Pennsylvania Health System. Adults over 55 years were assessed at baseline through surveys and a neurological examination. We recorded falls over the following 2 years. Parkinsonian signs were defined as the presence of 2 of 4 cardinal signs. Incident falls were compared between subjects with and without parkinsonian signs, and modified Poisson regression used to adjust for potential confounders in the relationship between parkinsonian signs and falls. RESULTS: 982 subjects with a mean age of 68 (s.d. 8.8) years participated. 29% of participants fell and 12% exhibited parkinsonian signs at baseline. The unadjusted RR for falls among individuals with parkinsonian signs was 1.36 (95% CI 1.05-1.76, p=0.02). After adjusting for age, cognitive function, urinary incontinence, depression, diabetes, stroke and arthritis, individuals with parkinsonian signs were still 38% more likely to fall than those without parkinsonian signs (RR 1.38, 95% CI 1.04-1.82; p=0.03). Falls among those with parkinsonian signs were more likely to lead to injury (53% vs 37%; p=0.04). CONCLUSIONS: Parkinsonian signs are a significant, independent risk factor for falls. Early detection of this clinical state is important in order to implement fall prevention programs among primary care patients.

Fostering interpersonal trust on social media: physicians' perspectives and experiences.

BACKGROUND: The problem of developing and sustaining mutual trust is one of the main barriers to knowledge sharing on social media platforms such as blogs, wikis, micro-blogs and social networking websites. While many studies argue that mutual trust is necessary for online communication and knowledge sharing, few have actually explored and demonstrated how physicians can establish and sustain trusted relationships on social media. OBJECTIVES: To identify approaches through which physicians establish interpersonal trust on social media. METHODS: Twenty-four physicians, who were active users of social media, were interviewed using a semi-structured approach between 2013 and 2014. Snowball sampling was employed for participant recruitment. The data were analysed using a thematic analysis approach. RESULTS: Physicians trust their peers on social media in a slightly different way than in face-to-face communication. The study found that the majority of participants established trust on social media mainly through previous personal interaction, authenticity and relevancy of voice, professional standing, consistency of communication, peer recommendation, and non-anonymous and moderated sites. CONCLUSIONS: Healthcare professionals need to approach social media carefully when using it for knowledge sharing, networking and developing trusted relations with like-minded peers.

Social media and physicians: Exploring the benefits and challenges.

Healthcare professionals' use of social media platforms, such as blogs, wikis, and social networking web sites has grown considerably in recent years. However, few studies have explored the perspectives and experiences of physicians in adopting social media in healthcare. This article aims to identify the potential benefits and challenges of adopting social media by physicians and demonstrates this by presenting findings from a survey conducted with physicians. A qualitative survey design was employed to achieve the research goal. Semi-structured interviews were conducted with 24 physicians from around the world who were active users of social media. The data were analyzed using the thematic analysis approach. The study revealed six main reasons and six major challenges for physicians adopting social media. The main reasons to join social media were as follows: staying connected with colleagues, reaching out and networking with the wider community, sharing knowledge, engaging in continued medical education, benchmarking, and branding. The main challenges of adopting social media by physicians were also as follows: maintaining confidentiality, lack of active participation, finding time, lack of trust, workplace acceptance and support, and information anarchy. By revealing the main benefits as well as the challenges of adopting social media by physicians, the study provides an opportunity for healthcare professionals to better understand the scope and impact of social media in healthcare, and assists them to adopt and harness social media effectively, and maximize the benefits for the specific needs of the clinical community.

Diurnal Glycemic Patterns during an 8-Week Open-Label Proof-of-Concept Trial of Empagliflozin in Type 1 Diabetes.

BACKGROUND: We recently reported improved glycemic control with reduced insulin dose in subjects with type 1 diabetes treated with the sodium glucose co-transporter-2 inhibitor empagliflozin. To further characterize the effects, we analyzed diurnal glycemic patterns by continuous glucose monitoring (CGM). METHODS: In an 8-week single-arm open-label pilot study of empagliflozin, we compared ambulatory glucose profiles produced from CGM data during 2-week intervals in a placebo run-in baseline period, end-of-treatment, and post-treatment. Change in glycemic exposure was evaluated by area under the median curve according to time of day (AUCTOTAL 12:00am-11:55pm; AUCDAY 7:05am-10:55pm, AUCNIGHT 11:00pm-7:00am), as well as glycemic variability, glycemic stability and time-in-target (≥70 to ≤140mg/dL). RESULTS: The 40 patients (26 on insulin pump) were aged 24±5 years and BMI 24.5±3.2 kg/m2. Consistent with the observed HbA1c decrease (8.0±0.9% to 7.6±0.9%, p<0.0001), normalized AUCTOTAL CGM decreased from 153.7±25.4 to 149.0±30.2mg/dL∙h at end-of-treatment (p = 0.31), and significantly increased post-treatment (164.1±29.5mg/dL∙h, p = 0.02). The numerical decrease in normalized AUCNIGHT (152.0±36.6 to 141.9±34.4mg/dL∙h, p = 0.13) exceeded AUCDAY (154.5±24.5 to 152.6±30.4mg/dL∙h, p = 0.65). Trends toward lower glycemic variability (83.1±18.9 to 75.6±28.6mg/dL, p = 0.06) and little change in glycemic stability (10.8±3.6 to 10.3±4.5mg/dL/h, p = 0.51) were observed. When empagliflozin was discontinued, these worsened relative to baseline (89.3±19.3mg/dL, p = 0.04 and 11.8±3.7mg/dL/hr, p = 0.08). Time-in-target numerically increased (40.2±11.9 to 43.1±13.5%, p = 0.69) at end-of-treatment but reversed post-treatment. Findings were similar on stratification of pump and MDI subjects. CONCLUSIONS: We observed that empagliflozin was associated with patterns of improved nighttime glycemia more prominent than daytime. TRIAL REGISTRATION: Clinicaltrials.gov NCT01392560.

Evaluation of a clinical tool to test and adjust the programmed overnight basal profiles for insulin pump therapy: a pilot study.

OBJECTIVE: Clinical protocols for basal rate testing and adjustment are needed for effective insulin pump therapy. We evaluated the effects of a continuous glucose monitoring (CGM)-based semiautomated basal algorithm on glycemia. METHODS: We developed and piloted a basal rate analyzer that interpreted CGM data from overnight fasts and recommended dose changes for subsequent nights. Subjects uploaded data online using sensor-augmented pumps for evaluation by the analyzer after each of 5 overnight fasts conducted over 2 to 8 weeks. It was designed to be conservative and iterative, making changes that did not exceed 10% at each iteration. The standard deviation and interquartile range of CGM values from midnight to 7 am (SD12-7am and IQR12-7am) over 3 baseline and 3 postintervention nights, hypoglycemia incidence (CGM values <4.0 mmol/L), and glycated hemoglobin (A1C) were compared. RESULTS: Twenty subjects with mean ages of 38±13 years and A1C 7.6%±0.8% (60±8.7 mmol/mol) underwent the 5 iterations of basal assessments over 5±3 weeks. SD12-7am and IQR12-7am did not change from baseline to postintervention (1.57±0.8 to 1.63±0.8 mmol/L; p=0.35; 3.66±2.07 to 3.47±2.26 mmol/L; p=0.90). However, mean glucose values were lower between 2 to 3 am at baseline compared to postintervention; 3-night hypoglycemia incidence declined from 1.6±1.8 to 0.5±0.7 episodes (p=0.01), and A1C improved from 7.6%±0.8% to 7.4%±0.9% (60%±8.7% to 57%±9.8% mmol/mol; p=0.03). CONCLUSIONS: The use of a basal rate analyzer was associated with reduced hypoglycemia and improved A1C. However, overnight glycemic stability was not improved. Further research into the efficacy of the CGM-based semiautomated algorithm is warranted.

Sodium-glucose cotransporter 2 inhibition and glycemic control in type 1 diabetes: results of an 8-week open-label proof-of-concept trial.

OBJECTIVE: Adjunctive-to-insulin therapy with sodium-glucose cotransporter 2 (SGLT2) inhibition may improve glycemic control in type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: We evaluated the glycemic efficacy and safety of empagliflozin 25 mg daily in 40 patients treated for 8 weeks in a single-arm open-label proof-of-concept trial (NCT01392560). RESULTS: Mean A1C decreased from 8.0 ± 0.9% (64 ± 10 mmol/mol) to 7.6 ± 0.9% (60 ± 10 mmol/mol) (P < 0.0001), fasting glucose from 9.0 ± 4.3 to 7.0 ± 3.2 mmol/L (P = 0.008), symptomatic hypoglycemia (<3.0 mmol/L) from 0.12 to 0.04 events per patient per day (P = 0.0004), and daily insulin dose from 54.7 ± 20.4 to 45.8 ± 18.8 units/day (P < 0.0001). Mean urinary excretion of glucose increased from 19 ± 19 to 134 ± 61 g/day (P < 0.0001). Weight decreased from 72.6 ± 12.7 to 70.0 ± 12.3 kg (P < 0.0001), and waist circumference decreased from 82.9 ± 8.7 to 79.1 ± 8.0 cm (P < 0.0001). CONCLUSIONS: This proof-of-concept study strongly supports a randomized clinical trial of adjunctive-to-insulin empagliflozin in patients with T1D.

Deus ex machina: the use of technology in type 1 diabetes.

Deus ex machina: in ancient Greek theatre, towards the end of a performance, a crane-like device was often used to lower an actor playing a god onto the stage in order to solve an apparently intractable problem in a plot-line. Nowadays, perceived wisdom believes that difficult clinical scenarios in diabetes can be alleviated by the introduction of technologies such as insulin pump therapy and glucose sensing. This "God from the Machine" approach to problem solving has been enthusiastically embraced by a small number of enthusiasts within the diabetes care community but access to these technologies is still very limited in the UK. The question is can the use of technology reduce or even eliminate the biological and psychological variables that prevent people living with diabetes achieving the standard of blood glucose control desired and if so should availability be more widespread?